PROJECT SUMMARY Follicular lymphoma (FL) is an indolent form of non-Hodgkin?s lymphoma, that arises from B lymphocytes and accounts for ~25% of NHL cases that is presently considered an incurable disease. Intratumoral application [to within diseased lymph nodes (LNs)] of immunotherapy drugs when used in combination with radiation therapy potently induces the abscopal effect, which is an attractive approach given the systemic nature of FL. However, given the toxicity risks of radiation therapy and invasive nature of intratumoral drug administration, new therapeutic approaches are crucially needed. The objective of this R01 program is to develop and validate a temporally controlled, two-stage drug delivery technology targeting lymphoma-bearing LNs for FL therapy. This will be tested in a rigorous preclinical model of Bcl6 and EZH2-driven lymphoma which is an animal model that most closely resembles human disease. Three aims are proposed: Aim 1: LN delivery and effects of immune stimulatory agents. Aim 2: LN delivery and effects of drugs inducing immunogenic cell death (ICD). Aim 3: Combined delivery of immune stimulatory and ICD-inducing agents in the Bcl6-EZH2 lymphoma model. This project is expected to yield several outcomes. First, these studies will define parameters for enhancing the efficacy of FL therapy via LN drug targeting. Second, the potential for LN-targeted therapy to improve the abscopal effect in the treatment of FL will be established. Therapeutic agents already in human clinical testing or approved for human use will be investigated in this work to ensure the highest potential for rapid clinical translation.